Tumor associated monoclonal antibodies (mAb's) are potential therapeutic agents as selective carriers of cytotoxic agents to malignant cells. This hypothesis is tested in animal model systems with mAbs directed toward antigens associated with a variety of malignancies. The cytocidal agents employed are radionuclides and their relative efficacy is evaluated in appropriate murine tumor model systems. The radionuclides chosen for study span the range of radionuclidic properties available thereby assaying the effects of emission energy, half-life, and type of emission. Current research is focused on performing extensive pre-clinical studies with a-particle emitting radionuclides 212,203Pb, 212,213Bi,and 211At. Ongoing clinical trials currently employ the second generation bifunctional chelating agent 1B4M-DTPA (aka MX-DTPA or Tiuxetan) for sequestering 90Y and or the CHX-A'' DTPA for 90Y and / or 213Bi. Both are suitable for scintigraphy with either 111In or PET imaging with 86Y. The chelation chemistry for 213Bi is established and is employed now is pre-clinical and clinical studies (vide infra).Pre-clinical results in the ongoing development of novel bifunctional chelating agents and linkers for targeted radiotherapy with isotopes of interest for Nuclear Medicine applications continues particularly in regards for resolution of high stability with reasonably acceptable formation rates. Novel ligands have been prepared and in vivo evaluations continue to assess the scope of utility of these chelating agents for both radio-lanthanides and a-particle emitting radionuclides such as 213Bi. Studies with 211At have yielded a novel protein modification reagent termed SAPS wherein the linking moiety has been removed from being the traditional aryl carboxylate active ester and placed several atoms away from the aryl astatine bond. Pre-clinical studies with this novel reagent termed SAPS conjugated to humanized monoclonal antibody anti-Tac indicate this agent to be stable in vivo and equivalent to indirectly radio-iodinated protein. Currently studies are ongoing to assess not only this permutation to increase the C-At bond strength, but to also provide a dative bond pi donor system with appropriate donor heteroatoms ortho to the At labeling site. A highly extensive and focused pre-clinical investigation into the use of both 212Bi and 212Pb-212 and b-emitting lanthanide radionuclides was initiated for the treatment of disseminated intraperitoneal disease such as that arising from either ovarian and pancreatic cancer. In addition to the use of these radionuclides, their combination, the use of combined monoclonal antibodies to address tumor heterogeneity, and their combination with chemotherapeutics is being systematically investigated. This investigation rests on the hypothesis that single doses of a single, targeted radionuclide lacks a rational basis for cancer therapy and that only via combined modality will significant therapeutic success be achieved. Current results indicate that substantial increases in median life expectancy in murine models are possible with single doses of these isotopes conjugated to clinically relevant antibodies such as CC49DCH2 or Herceptin. Use of 212Pb in combination with Gemcitabine has shown the greatest therapeutic efficacy to data. Extension of this result to address fractionated dosing of both radiation and gemcitabine while investigating the combination of other chemotherapeutics with this isotope continues. Results have clearly indicated that use of 90Y is contraindicated in these models while 177Lu appears to be promising in preliminary experiments.